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Page 249 Nickoloff et al. Cancer Drug Resist 2021;4:244-63 I http://dx.doi.org/10.20517/cdr.2020.89

Cellular radiosensitivity and radioresistance
Many physical, biological, and environmental factors influence cell responses to ionizing radiation,
including those that determine the level and types of damage to cell components; cell state (proliferating
or quiescent, cell cycle phase); DDR signaling and DNA repair capacity; propensity for programmed
cell death; cellular “memory” of past adaptive exposure; and tissue macro- and microenvironments. For
example, RB status influences intrinsic radiosensitivity among individuals [95,96] , and such biomarkers
can be exploited to personalize radiotherapy treatment planning [97,98] . The physical natures of ionizing
radiation (photon vs. particle and large vs. small mass/charge) determine lesion spatial distributions,
[99]
reparability, and cytotoxicity. Nonetheless, as noted by Willers, Xia, and colleagues , “there is no absolute
resistance to radiation”. If enough radiation can be delivered, all tumor cells will be eradicated regardless
of environmental, genetic, or metabolic factors. The practical limitation, of course, is collateral damage
to normal tissue. Hence, any strategy that increases radiation dose to tumors, decreases doses to normal
tissues, increases tumor-specific cytotoxic effects of radiation, or protects normal tissue from unavoidable
exposure can improve therapeutic gain and/or reduce side effects.

Hypoxia
An important environmental factor that regulates DNA damage induction is oxygen level, which varies
among tumor types, within different regions of a tumor, and between tumor and normal tissue. Normal
tissue is well-oxygenated, but tumors are often hypoxic as they struggle to supply oxygen during their
rapid growth. To a degree, tumors adapt to the hypoxic state, for example, by stabilizing HIF1a, which
regulates oxygen metabolism and angiogenesis via vascular endothelial growth factor, among other
effects [100] . Although certain solid tumors are frequently characterized as “hypoxic”, e.g., head and neck and
pancreatic cancers, it is now clear that most solid tumors have hypoxic regions. The degree of hypoxia is
regulated by passive oxygen diffusion, creating somewhat stable oxygen gradients across tumor masses,
and by transient effects such as altered perfusion by tumor vasculature [100] . Given the importance of oxygen
for ROS production during irradiation (OER), hypoxic regions within tumors are naturally radioresistant;
this is a particularly vexing problem given that normal (well-oxygenated) tissue may suffer greater ROS
damage than adjacent tumors, reducing therapeutic gain. Several strategies have been proposed to mitigate
hypoxia-related radioresistance, including modulation of dose fractionation, inflammatory responses, and
hypoxia itself [101,102] . For example, investigators have explored hyperbaric oxygen to radiosensitize tumors,
[3]
and tourniquets to promote normal tissue radioresistance, but these approaches have fallen out of favor .
Another idea is to mimic oxygen with agents such as nitroimidazoles, which radiosensitize hypoxic tumors.
Although these are effective, clinical use has been restricted because of associated neurotoxicity [103,104] .

CELL PROLIFERATION RATES
Solid tumors comprise rapidly growing (“bulk”) tumor cells and small numbers of so-called cancer stem
cells (CSCs). Much of tumor sensitivity to genotoxic chemo- and radiotherapeutics reflects the fact that
rapidly dividing, bulk tumor cells are more sensitive to DNA damage than most (non-dividing) normal
cells. CSCs, similar to normal stem cells, divide more slowly than bulk tumor cells, hence CSCs are
naturally radioresistant. Because CSCs are tumor-initiating cells that support both local tumor growth and
seed distant metastases, CSC radioresistance is a significant barrier to durable chemo- and radiotherapy
treatment responses [105-107] . Similar to CSCs, some tumor cells may be quiescent; tumor dormancy is seen
locally and at metastatic sites, it can be induced by therapy, and it confers radioresistance [108] . Changing
fractions of bulk, CSC, and quiescent tumor cells may cause regional variations in tumor radioresistance,
complicating radiotherapy treatment planning.

Hyperthermia
The sensitizing effects of hyperthermia have long been investigated in vitro and in pre-clinical models, but
it has not yet advanced to clinical practice [109] . Hyperthermia alters tissue perfusion to mitigate hypoxia,